The present invention concerns novel ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory substance having a carboxylic acid function, process for their preparation and pharmaceutical compositions containing them.
The novel esters according to the invention are prodrugs of the corresponding non-steroidal anti-inflammatory substances. In the context of the present specification the term "prodrug" denotes a derivative of a known and proven prior art non-steroidal anti-inflammatory substance having a carboxylic acid function such as for example 2-(acetyl)salicyclic acid (Aspirin), compounds known by their generic names indomethacin, ibuprofen, naproxen, diclofenac and the like, which derivatives when administered orally cleave in such a manner as to release the proven anti-inflammatory compound in its carboxylic acid form at its target site or sites of activity. The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug, i.e. the conventional non-steroidal anti-inflammatory substance is released. The remaining cleaved moiety is non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced such as ethanol, CO.sub.2 and acetaldehyde.
It is known that the non-ionized form of a drug is absorbed more efficiently than its ionic species. In the case of non-steroidal anti-inflammatory drugs containing a carboxylic acid function such as those known by the generic names indomethacin, naproxen, ibuprofen, diclofenac and the like the carboxylic acid is significantly ionized at physiological pH. The result is that such non-steroidal anti-inflammatory drugs are poorly absorbed through lipid-water membrane barriers and are irritating to the mucous membrane of the intestinal tract.
Laid open European Patent Application No. 81103066.7, Publication No. 0039051, of Apr. 23, 1981 in the name of Merck and Co. Inc. discloses novel prodrug forms of known non steroidal anti-inflammatory agents have a free carboxylic acid function, which are acetohydroxamic acid derivatives of the formula ##STR3## wherein ##STR4## is the acyl residue of any non-steroidal anti-inflammatory substance containing a carboxylic acid function, R.sub.1 and R.sub.2 stand for a variety of organic radicals and may also form together with the nitrogen atom to which they are attached a heterocyclic ring, and R.sub.3 stands for hydrogen or a variety of organic radicals. However, these prodrugs are of a rather complex nature and are not readily accessible. Thus the process for the preparation of these prodrugs as described in the said European patent application comprises four stages. In the first of these a non-steroidal anti-inflammatory agent having a free carboxylic acid function is converted into the corresponding acid chloride, e.g. by reaction with thionyl chloride. In a second stage the resulting acid chloride is reacted with hydroxyl amine to form a corresponding hydroxamic acid. The latter is then reacted with an aldehyde and the resulting reaction product is reacted with a secondary amine (See pages 14 and 15 of the European patent application).
In addition to the chemical complexity of the prodrug forms of non-steroidal anti-inflammatory substances according to the said European patent application, it is also difficult to predict which of the large variety of acetohydroxamic acid moieties is of sufficiently low toxicity and yields metabolites of sufficiently low toxicity as to be harmless upon cleavage of the prodrug in the body of a mammal.
It is accordingly the object of the present invention to provide novel, improved prodrug forms of known non-steroidal anti-inflammatory substances having a carboxylic function. It is a further object of the present invention to provide non-steroidal anti-inflammatory agents of reduced ulcerogenicity.
It is known from the literature, e.g. from British Patent Specification No. 1,363,506 of Sept. 15, 1971, to convert .alpha.-amino penicillins and penicillin G into the corresponding 1'-ethoxycarbonyloxy ethyl esters and it has been found that the absorption of such esters from the intestinal tract is superior to the absorption of a corresponding penicillin in the free acid form. However, the art of anti-bacterial and the antibiotic drugs is different from that of non-steroidal anti-inflammatory agents and the knowledge of the said penicillin esters did not induce people versed in the art of anti-inflammatory agents to look for prodrugs in the form of ethoxycarbonyloxy ethyl esters as manifested by the said European Patent Application No. 81103066.7 which was filed about ten years later.